"Glaucomas" are a group of debilitating eye diseases that are the leading cause of blindness subject to positive intervention in the United States and other developed nations. The term "glaucoma" actually encompasses a variety of ophthalmic disease states which are caused by distinct disease processes or pathological conditions of the eye. The disease states under the term "glaucoma" generally share the characteristic of having elevated intraocular pressure ("IOP"), which is a major risk factor in producing visual field loss and blindness. Of the many different ophthalmic disease states, Chandler et al (Glaucoma, 3d Ed., Lea and Febliger, Philadelphia (1986)) describe the following forms: primary open-angle glaucoma ("POAG"), progressive low-tension glaucoma, exfoliation and open-angle glaucoma ("OAG"), amylodosis and open-angle glaucoma, pigment dispersion and pigmentary glaucoma, angle-closure glaucoma, combined open-angle and angle-closure glaucoma, malignant glaucoma, angle-closure glaucoma after scleral buckling operations for separated retina, angle-closure glaucoma due to a multiple cyst of iris and ciliary body, angle-closure glaucoma secondary to occlusion of the central retinal vein, angle-closure glaucoma secondary to bilateral transitory myopia, glaucoma from perforating injuries, glaucoma from contusion of the eye, hemolytic or ghost-cell glaucoma, glaucoma associated with congenital and spontaneous dislocations of the lens, lens-induced glaucoma, glaucoma in aphasia, glaucoma due to intraocular inflammation, neovascular glaucoma, glaucoma associated with extra ocular venous congestion, essential atrophy of the iris with glaucoma, corticosteroid glaucoma, glaucoma after penetrating keratoplasty and characteristically unilateral glaucomas. In almost all cases, the IOP found in these glaucoma syndromes results from an increase in aqueous outflow resistance (see, Vaughan, D. et al., In: General Ophthamology, Appleton & Lange, Norwalk, Conn., pp. 213-230 (1992)).
Primary open-angle glaucoma ("POAG"), also termed chronic open-angle glaucoma ("COAG"), is the most prevalent form of glaucoma. The incidence of this condition in persons over the age of forty is about 0.4-0.5%. (Leske, M. C. et al., Amer. J. Epidemiol . 113:1843-1846 (1986); Bengtsson, B., Br. J. Ophthamol. 73:483-487 (1989); Strong, N. P., Ophthal. Physiol. Opt. 12:3-7 (1992)). Moreover, the prevalence of the disease rises with age to over 6% of those 75 years or older (Strong, N. P., Ophthal. Physiol. Opt. 12:3-7 (1992)). POAG is characterized by the loss of trabecular meshwork endothelial cells which is associated with degeneration of the normal structure of the trabecular meshwork. This degeneration leads to the obstruction of the normal ability of aqueous humor to leave the eye (see, Vaughan, D. et al, In: General Ophthamology, Appleton & Lange, Norwalk, Conn., pp. 213-230 (1992)).
In ordinary terminology, glaucoma is called "primary" if the pathogenic defect is believed to occur primarily within the tissue itself and without an obvious outside causal mechanism which can be defined for "secondary" glaucomas (e.g., see McGraw-Hill Encyclopedia of Science and Technology, 6th Ed., Vol. 8, p. 131 (McGraw-Hill 1987). In both POAG (for which no precise cause is known, although toxic substances produced locally and/or from the aqueous humor are believed to account for trabecular cell damage/death) and pigmentary glaucoma (often classified as a secondary glaucoma since the pigment or other debris from the posterior iris is thought to produce damage when engulfed by trabecular meshwork cells) there is known to be a marked loss of the endothelial cells of the meshwork. It is possible that oxidation products play a role in producing damage in the trabecular meshwork in both of these conditions, as well as in ocular iron toxicity, which can also produce a glaucoma. It would be very important to protect trabecular meshwork endothelial cells from injury and death which occurs in the disease processes. A loss in the number of trabecular meshwork cells and alteration in the function of the remaining cells is believed to be responsible for a decrease in the normal ability of aqueous humor to leave the eye, leading to decreased outflow facility (increased outflow resistance), and elevated IOP.
It previously has been demonstrated that aging itself leads to a progressive loss of human trabecular meshwork cells which also eventually leads to a compromise of the meshwork structure over time. Indeed, increased outflow resistance appears to occur in the non-glaucomatous aging population, and a method to preserve the cells in an aging normal individual as well as those with a recognized chronic glaucoma syndrome would be highly desirable. For these reasons, it would be desirable to have a means of treating or preventing pathological changes such as trabecular meshwork endothelial cell loss which are associated with the development and progression of these glaucoma syndromes. The present invention provides such improved therapeutic agents and methods.
Elevated IOP results in progressive visual loss and blindness if not treated appropriately and in a timely fashion. The normal IOP for humans usually measures 10-20 mm Hg (1.3-2.7 kilopascals) and is maintained by a balance between the aqueous inflow and outflow; with rare exceptions, all glaucoma syndromes being associated with an outflow defect. The aqueous humor is produced by the ciliary body in the eye and passes from the posterior chamber through the papillary space into the anterior chamber. The aqueous drains through the trabecular meshwork into Schlemm's canal, through which it leaves the eye. Elevated IOP is considered a major risk factor in producing damage to the optic nerve head, leading to loss of visual fields and eventually to blindness in many patients. Even in so called "normal tension glaucoma," lowering of an apparently normal IOP is thought to help prevent visual loss.
In the currently available treatments for glaucoma, one attempts to symptomatically lower the IOP by decreasing the amount of inflow (decreasing the rate of aqueous formation) or by increasing the facility of outflow. Although outflow can be increased by a variety of drugs, as will be appreciated, the available treatments do not address the underlying pathogenic processes in POAG, pigmentary glaucoma and other syndromes associated with cell loss (nor do they address the trabecular meshwork cell loss associated with normal aging).
Examples of various drug treatments that symptomatically reduce IOP (see, e.g., Babcock, J. C. et al., U.S. Pat. No. 5,124,154; Epstein, D. L., U.S. Pat. No. 4,757,089; Doulakas, J., U.S. Pat. No. 4,829,088) include: pilocarpine and epheneprine, which owe their effectiveness to increasing the facility of outflow; as well as timolol and other beta blockers, carbonic-anhydrase-inhibiting drugs, and alpha adrenergic agents, which owe their effectiveness to decreasing the rate of formation of aqueous.
Doulakas (U.S. Pat. No. 4,829,088) discloses the use of an ophthalmic medicament containing diclofenac-sodium in aqueous solution for the treatment of inflammations of the eye. Diclofenac-sodium is a non-steroidal anti-inflammatory ("NSAI") agent which is believed to be an alternative to corticosteroids (glucocorticoids) for the treatment of some inflammatory symptoms in the eye, and appears especially useful for the symptomatic relief of pain. The aqueous solution is made suitable for the local treatment of inflammations of the eye due to its stability against chemical decomposition of the diclofenac-sodium and preservation properties and toleration by the eye.
Nagy (U.S. Pat. No. 4,960,799) discloses aqueous ophthalmic solutions containing diclofenac-sodium. The solutions, having a pH of about 7.8, comprise per milliliter of solution about 0.1 to about 5.0 milligrams of (a) pharmaceutically acceptable salt of ortho-(2,6-dichlophenyl-)aminophenyl acetic acid; (b) about 0.1 to about 10 milligrams of a pharmaceutically acceptable sale of ethylene diamine tetraccetic acid, (c) about 0.5 to about 200 milligrams of a pharmaceutically acceptable solubilizer, (d) about 0.01 to about 5.0 milligrams of a pharmaceutically acceptable bacteriostat and (e) the remainder water. The ophthalmic solutions are used for topical administration to the eye for the control or treatment of ocular inflammation.
Cherng-Chyi et al. (U.S. Pat. No. 5,110,493) relates to ophthalmic non-steroidal anti-inflammatory drug formulations containing a quaternary ammonium preservative and a non-ionic surfactant. The formulations are useful for treating diseases that are either caused by, associated with or accompanied by inflammatory processes.
The above, and others in the well-known class of NSAI agents have been proposed to suppress signs of inflammatory responses, to prevent particular side-effects of surgical trauma, especially fluid accumulating in the back of the eye, and the appearance of inflammatory cells and vessel leakage in the anterior chamber. NSAI agents useful in treating inflammation are known to inhibit prostaglandin production and also to affect other eicosanoid pathways. NSAI agents are believed to be a possible alternative for glucocorticoids to reduce inflammation and avoid side-effects due to these drugs (e.g., concealing the risk of deterioration as a result of bacterial or viral infection), but in practice, NSAI agents have proven to be much less effective in treating many different types of ocular inflammation.
There is no NSAI agent that has been proposed to overcome the loss of trabecular cells associated with normal aging, nor in conditions in which cell loss and cell damage appear greater--as in POAG, pigmentary glaucoma and some other glaucoma syndromes. Preventing or treating loss of trabecular cells is particularly important since the IOP control in many glaucomatous patients eventually becomes a problem, which, even with optimal medical and surgical therapy, may lead to progressive visual loss. It also has been demonstrated that aging itself leads to a progressive loss of human trabecular meshwork cells which will eventually lead to a compromise of the meshwork over time. Indeed, increased outflow resistance appears to occur in the non-glaucomatous aging population, and a method to preserve the cells in an aging normal individual as well as those with a recognized chronic glaucoma syndrome would be highly desirable. For these reasons, it would be desirable to have a means of treating or preventing pathological changes such as trabecular meshwork endothelial cell loss which are associated with the development and progression of these glaucoma syndromes. The present invention provides such improved therapeutic agents and methods.